Usp21, a member of the ubiquitin protease family, plays a vital role in various biological functions. However, the effects of Usp21 dysfunction remain incompletely understood. In this study, we generated Usp21 knockout (KO) mice. Blood tests showed no impairment of liver function but did reveal elevated levels of total cholesterol (T-CHOL) and free fatty acid (FFA) in Usp21 KO mice compared to wild-type (WT) mice. Next, we performed RNA-sequencing (RNA-seq) to identify genes that Usp21 regulates. The results highlighted several candidate genes based on their biological relevance, and their expression levels were validated by RT-qPCR. The Usp21 KO mice exhibited significant elevations in the expression of the genes Fabp7, Nlrc5, and Ppargc1a, which play an important role in lipid metabolism, compared to WT. These data suggest that Usp21 may play roles in lipid metabolism in association with Fabp7, Nlrc5 and Ppargc1a. To clarify the involvement of USP21 in human hypercholesterolemia, we examined single-nucleotide polymorphisms (SNPs) around USP21 in non-hypercholesterolemic and hypercholesterolemic outpatients. We found that the rs11421 SNP downstream of USP21 was significantly associated with hypercholesterolemia. These data suggest that Usp21 plays a role in mice and human lipid metabolism and that its polymorphism may be a diagnostic marker for human hypercholesterolemia.

The Mediator complex is a central regulator of eukaryotic transcription, functioning as a dynamic molecular interface between gene-specific transcription factors and RNA polymerase II (Pol II). Although its overall architecture and general role in transcription have been extensively reviewed, accumulating genetic, genomic, and clinical evidence indicates that individual Mediator subunits make distinct and non-redundant contributions to human physiology and disease. In this review, we move beyond a generic description of Mediator function and present a subunit-resolved synthesis of Mediator biology with an emphasis on disease pathogenesis. A key feature of this review is a comprehensive table integrating disease associations and molecular functions of individual human Mediator subunits, enabling rapid assessment of functional specialization across the complex. We further discuss chromatin-based mechanisms of Mediator action, including cooperation with cohesin and architectural factors to regulate enhancer-promoter communication and higher-order genome organization. By organizing recent structural, mechanistic, and pathological findings into a unified framework, this review highlights how disruption of specific Mediator subunits contributes to cancer, developmental disorders, and metabolic disease, and outlines emerging opportunities for therapeutic intervention.

The Mediator complex is a central regulator of eukaryotic transcription, functioning as a dynamic molecular bridge between gene-specific transcription factors and RNA polymerase II (Pol II). Although decades of research have established its modular architecture and fundamental role in transcriptional control, recent advances have significantly expanded our understanding of its structural conformations, subunit-specific functions, and links to human disease. This review provides a comprehensive overview of the Mediator complex, highlighting key structural and functional discoveries from the past decade and synthesizing its diverse roles in transcriptional regulation. We further discuss emerging concepts and future directions for therapeutically targeting Mediator, particularly in cancer. Together, these insights position the Mediator complex as a highly conserved yet adaptable, signal-responsive regulatory hub with broad implications for both normal physiology and disease pathogenesis.

USP21, a member of the ubiquitin protease family, plays a vital role in various biological functions. However, the effects of USP21 dysfunction have yet to be fully understood. Here, we generated Usp21 knockout (KO) mice and conducted microarray to identify genes that Usp21 regulates. Its results raised several genes based on their biological characteristics, and RT-qPCR confirmed their expression. KO mice exhibited significant elevations in the expression of the genes Fabp7 and Nlrc5, which play a role in lipid metabolisms, compared to wild-type mice. Blood tests showed no impairment of liver function but did reveal elevated levels of total cholesterol and free fatty acids in KO mice compared to wild-type mice. These data suggest that Usp21 may play roles in lipid metabolism associated with Fabp7 and Nlrc5. To clarify the involvement of USP21 in human hypercholesterolemia, we examined single nucleotide polymorphisms (SNPs) around USP21 in non-hypercholesterolemic and hypercholesterolemic outpatients. We found that the rs11421 SNP downstream of USP21 was associated with hypercholesterolemia. These data suggest that USP21 plays a role in mice and human lipid metabolism and that its polymorphism may be a diagnostic marker for human hypercholesterolemia.

Mediator complex subunit 19 (MED19), a component of the Mediator complex, has emerged as a potential regulator of cancer progression, although its downstream transcriptional programs remain poorly understood. Here, we investigated the role of MED19 across 20 human cancer cell lines. An siRNA-mediated knockdown (KD) screen identified A549 lung cancer and MCF-7 breast cancer cells as particularly sensitive to MED19 KD, exhibiting markedly reduced cell viability. Flow cytometric analysis revealed that MED19 KD induced G1-phase arrest, suggesting a role in G1/S-phase progression. RNA sequencing followed by differential expression, Gene Ontology (GO), and chromosomal mapping analyses identified amphiregulin (AREG) and cyclin-dependent kinase regulatory subunit 1B (CKS1B) as candidate downstream effectors in A549 and MCF-7 cells, respectively. Knockdown of AREG or CKS1B inhibited cell proliferation and recapitulated the G1-phase arrest induced by MED19 KD. Moreover, ectopic expression of AREG or CKS1B partially rescued the cell-cycle defects caused by MED19 KD. These findings identify MED19 as a context-dependent regulator of cancer cell proliferation and G1/S-phase progression through distinct downstream transcriptional programs in lung and breast cancer cells.